Member, Whitehead Institute
Director, Ludwig Center for Molecular Oncology
Massachusetts Institute of Technology
Breast cancer is a heterogeneous collection of diseases that respond in very different ways to treatments. Among the most difficult to treat are the triple-negative tumors, which are particularly aggressive and resistant to treatment. One important determinant of their malignant behavior – arguably the most important one – derives from a group of cancer cells within these tumors that exhibit “mesenchymal” traits –properties of cells that make them resistant to treatment and more likely to metastasize ( form new tumors at distant sites of the patient’s body). The alternative to mesenchymal cells are those that exhibit a more “epithelial” characteristic. These are far more benign and responsive to treatment. Dr. Weinberg’s team has discovered a way to convert mesenchymal breast cells, including those from breast cancer, to an epithelial state by manipulation of a protein called cAMP. By elevating the levels of this chemical within mammary cells of the mesenchymal type, they can force these cells to revert to an epithelial state. They are now examining precisely how cAMP succeeds in inducing breast cancer cells to become more epithelial in order to devise new means of making breast cancer cells susceptible to treatment by existing anti-breast cancer therapies.
Dr. Weinberg is a founding member of the Whitehead Institute for Biomedical Research and the Daniel K. Ludwig Professor for Cancer Research at the Massachusetts Institute of Technology (MIT). He is also the first Director of the Ludwig Cancer Center at MIT. He is an internationally recognized authority on the genetic basis of human cancer. Dr. Weinberg and his colleagues isolated the first human cancer-causing gene, the ras oncogene, and the first known tumor suppressor gene, Rb, the retinoblastoma gene. Research in Dr. Weinberg's laboratory is focused on attempting to elucidate the biochemical and cell-biological mechanisms that enable carcinoma cells in primary tumors to invade and disseminate, resulting in the formation of metastases in distant sites. Much of this work depends on analyses of the cell-biological program termed the epithelial-mesenchymal transition (EMT). In addition to conferring traits such as motility and invasiveness on epithelial carcinoma cells, activation of this program heightens their resistance to chemotherapeutic attack. In recent years the Weinberg laboratory has also found that activation of a previously latent EMT program places both normal and neoplastic epithelial cells in a position from which they can enter into a stemcell state. In the case of carcinomas, the tumor-initiating powers resulting from this shift indicates the formation of cancer stem cells (CSCs), which are qualified to serve as founders of new metastatic colonies in distant anatomical sites. Dr. Weinberg's research has increasingly focused on the interaction of CSCs with recruited inflammatory cells and on the later steps of the invasion-metastasis cascade that enables disseminated carcinoma cells to extravasate, thereby setting the stage for the formation of micro- and macroscopic metastatic colonies.